Thiolate-alkylating enzyme

ZnSR(TmXyl) (R = alkyl) complexes have been prepared to reproduce the S3Zn-SR coordination environment of thiolate-alkylating enzyme. The most reactive thiolate, ZnSHt(TmXyl)], reacts slowly with trimethyl phosphate yielding methyl-ethylthioether and... 

Zinc is the active metal in the largest group of metalloproteins found in the nature. Recently a new class of zinc enzymes with a sulfur-rich environment has emerged the thiolate-alkylating enzimes, the most prominent of which is the cobalamine-independent methionine synthase.126 For these reasons several monothiolate zinc complexes have been prepared for the modelling of these enzymes with different N2S as (13),127 130 N20,13° 132 N3,132,133 S3,134 tripod ligands, or with Cd because of the favourable spectroscopic properties with an S3 tripod ligand.135... 

A structural analog for the Cys4Zn motif of the ADA protein is constituted by the thiolate complex [ZnSPh(Tmph)].132 Related cadmium complexes have been also described.149 These studies are also pertinent to other enzymes that feature cysteine thiolate alkylation such as methionine synthase, methanohcoenzyme methyltransferase, farnesyl transferase. 

Several thiols occur naturally for example, skunk secretion contains 3-methyll-butanethiol and cut onions evolve 1-propanethiol, and the thiol group of the natural amino acid cysteine plays a vital role in the biochemistry of proteins and enzymes (see Introduction, p. 2). Primary and secondary thiols may be prepared from alkyl halides (RX) by reaction with excess sodium thiolate (SN2 nucleophilic substitution by HST) or via the Grignard reagent and reaction with sulfur. Tertiary thiols can be obtained in good yields by addition of hydrogen sulfide to a suitable alkene. Thiols can also be prepared by reduction of sulfonyl chlorides (Scheme l).la,2a... 

Alkyl halides are even less reactive than acyl halides, as indicated by the compilation of reaction rates of thiolate anions with various types of alkyl halides (282). Nevertheless, potentially useful affinity labels have been synthesized with alkyl halide substituents and have been shown to specifically inactivate several enzymes, albeit slowly the low reactivity of the alkyl halides may minimize nonspecific reaction. Adenosine 5 -(2-bromoethyl)phosphate has been characterized and reported to inactivate NAD -dependent isocitrate dehydrogenase (283). The 2 - and 3 -(2-bromoethyl)-AMP labels have also been synthesized, and model reactions of the bromoethyl-AMPs with cysteine, lysine, histidine, and tyrosine have been studied (284). More recently, esters of adenosine 5 -monophosphate have been prepared with ethyl, propyl, or hexyl moieties and bromo or chloro substituents at the w position (285). Yeast alcohol dehydrogenase exhibited enhanced inactivation by the hexyl derivative, but inactivation rates of other dehydrogenases were unremarkable. Two iodopropyl derivatives of cAMP have been described, namely, 1, A -(3-iodopropyleno)adenosine 3, 5 -cyclic monophosphate and 3 -0-(2-iodo-3-hydroxypropyl)adenosine 3, 5 -cyclic monophosphate the latter inactivates cAMP phosphodiesterase from human platelets, with a pseudo-first-order rate constant of 0.147 hr" (286). 

Cu(II) to yield a paramagnetic Cu(II)-thiolate complex/ Carbon dioxide coordinated to Ni(0) may be reduced to CO by R—SH (R = H, alkyl, benzyl, phenyll, or substituted phenyl) providing a model for carbon monoxide dehydrogenase enzyme. The disulfide generated in this reaction reacts further with the Ni(0) complex to give Ni(SR)2/ The kinetics of the reduction of Cr(VI) by l-methionine (represented by RSCH3) provides the rate law (45), with values for /c2... 

Baldwin has suggested that a C—H activation involving the formation of Fe—C bonds may be important in the biosynthesis of penicillin. In one model, the enzyme first forms the four-membered ring of penicillin. Then an iron 0x0 species abstracts an H atom from the substrate to leave a carbon-centered radical that in turn binds to the metal. A reductive elimination of a thiolate with the alkyl leads to the formation of the penicillin ring ... 

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